The long-term goal of this proposal is to develop systemic antifungal agents with minimal toxicity and preferable capabilities of being delivered orally. The immediate focus,.however, is to study the structure-activity relationship (SAR) of the natural product, Cryptolepine, in order to understand the structural characteristics and requirements for its antifungal activity. Cryptolepine was selected because of it's potency, water solubility, low toxicity and broad spectrum of activity against opportunistic infections associated with AIDS. Several structural analogues of cryptolepine will be synthesized to delineate the structural features int eh quindoline nucleus that contribute to activity and any toxicities associated with the drug. This information will be incorporated into a computer-assisted drug design of more potent and less toxic compounds as alternatives to Amphotericin B and 5-Fluorocytosine (5-FC). Graphical computer displays will aid visualization and comparison of t he 3-dimensional structures of the proposed compounds and other natural products with similar activity. The active-analog approach will be utilized in the identification and selection of pharmacophoric groups associated with antifungal activity. Each synthetic compound will be characterized spectroscopically and by elemental analysis, and then evaluated against C. neoformans, A. Fumigatus, M. Intracellular and C. Albicans using standard in-vitro antifungal assays. Promising new compounds will subsequently be evaluated for their physicochemical characteristics, i.e., pKa and Log P values, and then in vivo activity and toxicity in animal models.